Alzheimer disease (AD) is a progressive neurodegenerative disease and the most common cause for dementia in the elderly. Among patients with AD, the rate of disease progression varies considerably, related in some degree to stage of illness and comorbid medical conditions. Psychological stress is well known to increase activity of the hypothalamic-pituitary-adrenal (HP A) axis by promoting release of glucocorticoid (GC) hormones in a variety of mammalian species, and chronically increased levels of GC hormones have been associated with decreases in hippocampal volume and memory deficits. Associations between stress, increased GC activity and hippocampal degeneration may have special relevance for understanding the neurobiology of AD, since hippocampal degeneration is also a marker of early AD. However, there have been few investigations of the relationship between stress, GC hormones and the progression of AD. The overall aim of this project is to investigate the general hypothesis that stress, by increasing GC levels, accelerates the rate of progression of AD. In preliminary work, we have made two key findings that support this general hypothesis. First, in a study of patients with very mild-to-mild dementia of the Alzheimer type (DAT), we found a correlation between SAM serum cortisol concentrations and the rate of change of clinical and neuropsychological measures of dementia. Second, in Tg2576 mice that overproduce the human form of amyloid precursor protein (APP), chronic isolation stress increased serum levels of corticosterone, the severity of deficits in contextual memory, and the rate of deposition of a-amyloid plaques in the hippocampus and cortex. We now propose to further investigate the general hypothesis that stress can accelerate the rate of progression of AD via increases in GC activity. First, we propose to assess correlations between blood and salivary cortisol levels and the rate of disease progression in DAT subjects measured using neuroanatomical as well as clinical and neuropsychological measures. Second, we propose to investigate the mechanism(s) by which isolation stress increases the rate of beta-amyloid plaque deposition in APP-transgenic mice, and in specific, to determine the degree to which GC hormones are an element of this mechanism.